Convergent Evolution of Calcineurin Pathway Roles in Thermotolerance and Virulence in Candida glabrata.
Convergent Evolution of Calcineurin Pathway Roles in Thermotolerance and Virulence in Candida glabrata.
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DOI：
10.1534/g3.112.002279
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发表时间：
2012-06
期刊：
影响因子：
--
通讯作者：
Heitman J
中科院分区：
文献类型：
--
作者：
Chen YL;Konieczka JH;Springer DJ;Bowen SE;Zhang J;Silao FG;Bungay AA;Bigol UG;Nicolas MG;Abraham SN;Thompson DA;Regev A;Heitman J
光滑念珠菌是一种新出现的人类真菌病原菌，经常耐药，导致免疫低下患者治疗困难和较高的死亡率。钙激活蛋白磷酸酶钙调神经磷酸酶通过在血清中存活或在宿主温度(37℃以上)下生长的不同机制，在控制不同真菌病原体的药物耐受性、菌丝生长和毒力方面发挥关键作用。在这里，我们全面研究了光肩星毛藻中钙调神经磷酸酶信号通路，发现了钙调神经磷酸酶及其下游靶基因Crz1在调节小鼠眼部、尿路和全身感染的耐热性、细胞内构筑和发病机制中的新的和未知的功能。这代表了钙调神经磷酸酶在人类主要真菌病原体耐热生长中作用的第二个独立来源，不同于在新生隐球菌中独立出现的作用。钙调神经磷酸酶还通过与白色念珠菌不同的机制促进血清中光滑念珠菌的存活，从而能够在小鼠全身感染模型中建立组织定植。为了更详细地了解钙调神经磷酸酶信号转导途径，我们进行了整体转录谱分析，并鉴定了光皮藻中依赖于钙调神经磷酸酶和Crz1的基因，这些基因参与了细胞壁的生物合成、热休克反应和钙调神经磷酸酶的功能。钙调神经磷酸酶调节剂(Rcn)是一类新的钙调神经磷酸酶修饰物家族，该家族的两个成员：Rcn1和Rcn2在光滑拟青霉中被鉴定出来。我们的研究表明，Rcn2的表达受钙调神经磷酸酶和Crz1的调控，在光肩星天牛钙耐受所需的回路中作为钙调神经磷酸酶的反馈抑制因子发挥作用。相反，钙调神经磷酸酶调节因子Rcn1激活了钙调神经磷酸酶信号。有趣的是，在小鼠全身感染模型中，Rcn1和Rcn2都不是毒力所必需的。综上所述，我们的研究结果表明，钙调神经磷酸酶信号在耐热性和毒力中起着关键作用，而Rcn1和Rcn2在控制光肩星天牛钙调神经磷酸酶信号方面具有相反的功能。
Candida glabrata is an emerging human fungal pathogen that is frequently drug tolerant, resulting in difficulties in treatment and a higher mortality in immunocompromised patients. The calcium-activated protein phosphatase calcineurin plays critical roles in controlling drug tolerance, hyphal growth, and virulence in diverse fungal pathogens via distinct mechanisms involving survival in serum or growth at host temperature (37° and higher). Here, we comprehensively studied the calcineurin signaling cascade in C. glabrata and found novel and uncharacterized functions of calcineurin and its downstream target Crz1 in governing thermotolerance, intracellular architecture, and pathogenesis in murine ocular, urinary tract, and systemic infections. This represents a second independent origin of a role for calcineurin in thermotolerant growth of a major human fungal pathogen, distinct from that which arose independently in Cryptococcus neoformans. Calcineurin also promotes survival of C. glabrata in serum via mechanisms distinct from C. albicans and thereby enables establishment of tissue colonization in a murine systemic infection model. To understand calcineurin signaling in detail, we performed global transcript profiling analysis and identified calcineurin- and Crz1-dependent genes in C. glabrata involved in cell wall biosynthesis, heat shock responses, and calcineurin function. Regulators of calcineurin (RCN) are a novel family of calcineurin modifiers, and two members of this family were identified in C. glabrata: Rcn1 and Rcn2. Our studies demonstrate that Rcn2 expression is controlled by calcineurin and Crz1 to function as a feedback inhibitor of calcineurin in a circuit required for calcium tolerance in C. glabrata. In contrast, the calcineurin regulator Rcn1 activates calcineurin signaling. Interestingly, neither Rcn1 nor Rcn2 is required for virulence in a murine systemic infection model. Taken together, our findings show that calcineurin signaling plays critical roles in thermotolerance and virulence, and that Rcn1 and Rcn2 have opposing functions in controlling calcineurin signaling in C. glabrata.
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影响因子：
4.2
作者：
Djalilian, AR;Smith, JA;Robinson, MR
通讯作者：
Robinson, MR
DOI：
10.1083/jcb.124.3.351
发表时间：
1994-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Cunningham KW;Fink GR
通讯作者：
Fink GR
影响因子：
11.4
作者：
Görlach, J;Fox, DS;Heitman, J
通讯作者：
Heitman, J
影响因子：
2.8
作者：
Jinhee, Choi;Kim, Yangseon;Lee, Yong-Hwan
通讯作者：
Lee, Yong-Hwan
影响因子：
3.1
作者：
Bader, Teresa;Schroeppel, Klaus;Morschhaeuser, Joachim
通讯作者：
Morschhaeuser, Joachim